This invention relates to pH and temperature sensitive terpolymers which are useful as carriers or coating materials for oral drug delivery. More particularly, this invention relates to terpolymers having pH sensitive, temperature sensitive and hydrophobic components. This class of terpolymers allows for drug-laden compositions to be orally ingested, pass through the acidic environment of the stomach and into the intestinal tract where the drugs are released in response to temperature and pH conditions.
Most polymeric controlled drug delivery systems have been developed to achieve desirable release rates. A zero-order (or constant-rate) of drug delivery is preferable to achieve optimal therapeutic effects. Zero-order release of a drug from monolithic polymer devices cannot generally be obtained because the drug concentration gradient within the polymer matrix falls with time. Various types of approaches have been developed to improve release rates. One approach includes introduction of a diffusional barrier on the surface of a polymer matrix. Lee et al, "Drug Release from Hydrogel Devices with Rate-Controlling Barriers", J. Membr. Sci., 7, 293-303 (1980), disclose methods for introducing rate-controlling barriers on the surface of monolithic hydrogel devices prepared from poly-HEMA (polyhydroxyethyl methacrylate) and a copolymer of HEMA and MEEMA (methoxyethoxyethyl methacrylate). The rate limiting barrier was produced in monolithic devices by soaking in an ethanolic solution of the crosslinking agent EGDMA (ethylene glycol dimethacrylate) followed by UV (ultraviolet) radiation. Release of progesterone from such devices in vitro was zero-order. A different method of improving release is to control hydrogel swelling. Hopfenberg et al., "Swelling-Controlled, Constant Rate Delivery Systems", Polym. Eng. Sci. 18 1186-1191 (1978) address materials and conditions required for in vitro constant rate absorption of a liquid into a glassy polymer to produce prototype devices for constant rate delivery of a solute (drug), molecularly dispersed within the polymer, to the surrounding liquid environment and discuss the development of such devices for the swelling-controlled release of drugs. In a similar vein, crystalline/glassy transition controlled release is discussed by Graham et al., "Hydrogels for Controlled Drug Delivery", Biomaterials 5, 27-36 (1984). Lee, "Novel Approach to Zero-order Drug Delivery Via Immobilized Nonuniform Drug Distribution in Glassy Hydrogels", J. Pharm. Sci. 73, 1344-1347 (1984) refers to improving release by means of a loading method utilizing a controlled-extraction process on initially dry, drug-loaded hydrogels to generate an inflection-point-containing drug concentration profile followed by a vacuum freeze-drying step to rapidly remove the swelling solvent and immobilize in situ a nonuniform drug distribution. An approach wherein the principal energy source governing the release of drugs from polymeric matrices is osmotic in nature is discussed by Gale et al, "Use of Osmotically Active Therapeutic Agents in Monolithic Systems", J. Memb. Sci. 2, 319-331 (1980). Mueller et al., "Gradient-IPN-Modified Hydrogel Beads: Their Synthesis by Diffusion-Polycondensation and Function as Controlled Drug Delivery Agents", J. App. Polym. Sci. 27, 4043-4064 (1982), discuss the utilization of osmotic and gradient effects in using IPN (interpenetrating polymer network) membranes and matrices to improve drug delivery rates. The use of heterogeneous interpenetrating polymer network matrices for the controlled release of drugs is further disclosed by Bae et al., U.S. Pat. No. 4,921,287 which issued Jun. 5, 1990. The network disclosed is a heterogeneous matrix formed from a hydrophilic component such as polyethylene oxide (PEO) or poly(N,N'-dimethyl acrylamide-co-styrene) (DMM.sub.m -co-styrene) and a hydrophobic component such as styrene, an alkyl methacrylate or polytetramethylene ether glycol. The relative amounts of the two components, or "domains", can be varied, as can the diffusivities and solubilities of the drug combinations to be loaded therein, to control and change, as desired, the time release profile of incorporated drug. The control of release from matrices by varying the geometry is disclosed by Hsieh, et al. "Zero-Order Controlled-Release Polymer Matrices for Micro- and Macromolecules", J. Pharm. Sci. 72, 17-22 (1983). These are but representative of numerous methods/and or devices which have been proposed as a means for improving delivery of orally ingested drug-laden compositions. However, approaches heretofore made generally suffer from complicated fabrication procedures which may not be economical, practical, and may not even be suitable for preparing polymers for oral drug delivery. One problem is that the release of the incorporated drug is at a predetermined rate regardless of environmental conditions. Perhaps even more detrimental is that the drug-laden polymer must pass through the high acidic environment of the stomach where the drug may be released and/or undergo rapid hydrolysis or, in the case of peptides and proteins, denaturation and hydrolysis.
Preferably, drugs in dosage forms for human applications should be incorporated into the carrier system using straightforward procedures under clean, nontoxic conditions to maintain the activity of the labile drugs. Drug incorporation is generally performed by the polymerization of monomeric materials in the presence of drugs, the solvent casting of drug polymer solutions or by a solvent sorption technique of polymerized and purified polymers. In the pre-polymer drug incorporation methods the purification of the final product is often neglected or impossible to accomplish. This leaves unreacted or other undesirable components in the product which may lead to difficulties in clinical applications. In cases of solvent casting or solvent sorption techniques, nontoxic solvents are used for drug/polymer dissolution or as the swelling agent. These methods are considered beneficial for some active agents in stable organic solvents. However, polypeptide or protein drugs undergo conformational changes or denaturation, even with relatively nontoxic alcoholic solutions.
Polymers showing lower critical solution temperature (LCST) in water are desirable for loading of bioactive polypeptides and proteins. This means that an aqueous polymer solution undergoes a phase separation (precipitation) when heated above it's LCST. This results in temperature sensitive polymers which are soluble in water at low temperatures but which are solidified at body temperature can act as carriers for protein and polypeptide type compounds. To minimize problems of hydrolysis or degradation in the stomach, it would also be desirable to block gastric drug release through the use of pH sensitive materials which are rigid or insoluble at stomach pH, thereby preventing drug release, but which will dissolve or swell in the normal physiological pH of the intestinal tract allowing drug release therein.
The formation of insoluble crosslinked hydrogel copolymers having both pH and temperature sensitive properties as carriers for bioactive agents of the protein or polypeptide category have recently been reported. Dong et al., "pH Sensitive Hydrogels Based on Thermally Reversible Gels for Enteric Drug Delivery", Proc. Intern. Symp. Control. Rel. Bioact. Mater., 16 95-96 (1989) and Park et al., "Synthesis, Characterization, and Application of pH/Temperature Sensitive Hydrogels", Proc. Intern. Symp. Control. Rel. Bioact. Mater., 17 112-113 (1990) refer to such hydrogel systems. Dong et al., show the incorporation of acrylic acid (AAc) into LCST heterogels formed from the combination of a 1/1 ratio of Poly(N-isopropylacrylamide), (NIPAAm) and vinyl terminated polydimethylsiloxane (VTPDMS). These hydrogels are stated to be sensitive to both pH and temperature when used as an insoluble matrix system for the enteric delivery of indomethacin, a non-steroid anti-inflammatory drug. Dong et al. prepared hydrogels having from 2 to 10 moles of AAc per 100 moles of NIPAAm. They found only moderate swelling of the gels at a pH of 1.4 but extensive swelling at pH of 7.4. Swelling increased with AAc content. Only negligible amounts of indomethacin were released at the gastric fluid pH of 1.4 but release increased at the higher pH. These copolymers were above their LCST at the physiological temperature of 37.degree. C. The release rate at pH 7.4 was relatively constant suggesting a swelling-controlled mechanism.
Park et al. state that for such hydrogels to function properly, the gel should exhibit a sharp volume change with small pH changes near physiological pH (7.4) and at body temperature (37.degree. C.). Park et al. prepared a series of pH sensitive, cationic copolymeric hydrogels, based on a thermally reversible hydrogel exhibiting a phase transition behavior, which were characterized in terms of pH-dependent swelling properties. The gels were prepared by the copolymerization of NIPAAm and N',N'-dimethylaminopropylmethacrylamide (DMAPMAAm) in various molar ratios in the presence of a small amount of a crosslinker. To test a self-regulated insulin release from this hydrogel matrix, insulin crystals and glucose oxidase were co-entrapped within a hydrogel matrix (97/3 molar ratio of NIPAAm/DMAPMAAm) which exhibited a pH-dependent phase transition at about pH 7.4 at 37.degree. C. as well as a temperature-dependent phase transition under the same conditions. Insulin release profiles from the hydrogel matrix were studied by modulating the external pH, glucose concentration, temperature and thermal cycling operation. The water content of the gel was found to be dependent on both pH and temperature with the gel swelling in the low pH region due to the ionic repulsion of the protonated amine groups and collapsing at high pH values because of unprotonated amine groups and the thermally-induced collapse of the neutral gel. It was found that insulin delivery from the gel was controlled by modulating temperature. However, there were neither pH nor glucose responsive insulin releases.
The copolymers reported by both Dong et al. and Park et al. are pH/temperature sensitive hydrogels formed using vinyl terminated polydimethylsiloxane (VTPDMS) which results in crosslinked and insoluble gels under any conditions. In other words, once formed by polymerization, the solubility of these gels cannot be changed. Therefore, these gels are sensitive to pH and temperature only by swelling characteristics and not by solubility parameters. Drugs or bioactive agents can be incorporated into these gels only by solvent sorption methods or by loading concurrently during the polymerization process. Thus, these polymers suffer the same disadvantages of drug incorporation and purification referred to above.
It has been found that the LCST of polymers is affected by comonomers in such a way that hydrophilic comonomers cause the LCST to occur at higher temperatures whereas hydrophobic comonomers lower the LCST. The result is that hydrophilic pH sensitive components affect the temperature sensitive polymer properties by shifting the LCST of a temperature sensitive polymer to higher temperatures. When the LCST is above the physiological body temperature (37.degree. C.), drug release from a hydrogel will not be controllable because of the increased solubility or swellability of the polymer. Also, there would be difficulties in the preparation of dosage forms of such formulations.
It would be desirable to provide pH and temperature sensitive polymers which are truly soluble at temperatures below their LCST, which counteract the effects of pH sensitive components on the LCST of the polymer, which can be prepared in relatively pure form and wherein the drug loading and final dosage form can be determined by a variety of techniques such as drop precipitation and coating.